Our laboratory proposes to develop methods for optimal study and control of pharmacokinetic systems. We propose to consider explicitly methods for computing optimally, and in a practical manner, the shape of the probability density functions of pharmacokinetic rate constants. We also propose to consider quantitatively the effects of the uncertainties in preparation of doses, laboratory assays, ward management, and phlebotomy schedules upon the precision with which a patient's serum drug concentrations can be controlled. We propose to consider mathematical cost functions associated with achievement of such control which accurately reflect the quantitative risks, and benefits that exist in each patient's clinical environment. This work should significantly increase our knowledge of (and ability to describe) the behavior of drugs in patients, and should increase the precision and safety of their care. It should also permit """"""""least-cost, least-effort"""""""" approaches to drug therapy, in which each measurement of a drug level is mathematically justified as needed to achieve the desired degree of precision, and no more are obtained than those needed to do the job. This work should also improve cancer chemotherapy, as we learn how to manage large pharmacokinetic models, appropriate to many anti-cancer drugs, which have many active metabolites in addition to their own activity. This work should also lead to better methods for the discovery, analysis, and management of drug interactions.
